The overall goals of this proposal are to determine the behavioral effects of CB2- cannabinoid receptor ligands and to analyze the expression of CB2-receptors (CB2Rs) in selected mouse brain regions. Cannabinoids are the constituents in marijuana and endocannabinoids (eCBs) are the natural endogenous marijuana-like substances found in animals and humans. There are two well characterized cannabinoid receptors (CB1Rs and CB2Rs) that are activated by cannabinoids and eCBs with multiple physiological roles, and consequently with potential therapeutic immunological, neurological and metabolic indications. CB1Rs have been well characterized and are known to be ubiquitously distributed in mammalian central nervous system (CNS) and peripheral tissues. However, the neuronal and functional expression of CB2Rs in the brain has been much less well studied and characterized. Since CB2Rs were originally found to be predominantly expressed in immune cells and associated with immune regulation and function, they were less investigated for CNS roles except for the association with brain cells of macrophage linage and were referred to as peripheral CB2Rs. Therefore, the CNS effects of CB2Rs had been ambiguous and controversial and little is known of their role in neuropsychiatric disorders. Indeed our preliminary studies provided the first evidence for neuronal CNS effects of CB2Rs and their possible role in schizophrenia, eating disorders, drug addiction, depression, and autism spectrum disorders. The hypothesis to be tested is that activation and inhibition of functional neuronal CB2Rs in the brain induces behavioral responses in locomotor activity and emotionality tests in the mice model. Therefore the specific aims of this project are: 1) to determine the behavioral effects of CB2R ligands; 2) to analyze the expression of CB2-Rs in brain regions of mice; and 3) engage undergraduates in the research and strengthen the research environment in a predominantly undergraduate institution that is not research intensive. We have developed a new antibody to test the specificity of neuronal CB2Rs in the brain. The findings will provide a deeper insight int the role of CB2Rs in the brain that should be considered in developing CB2R based therapeutic agents in pain, auto-immune, mental and neurodegenerative disorders. PUBLIC HEALTH RELEVANCE: Significant advances including the discovery that the human body and brain makes its own natural marijuana-like substances called endocannabinoids that act upon two types of receptors called CB1 and CB2 receptors have been achieved. Since little is known about the presence and function of CB2-receptors in brain neurons, we propose to study their role and potential therapeutic use of drugs acting on CB2-receptors in mental disorders.